Salts of benzimidazole derivative with amines and process for manufacturing the same

ABSTRACT

It is an object of the present invention to provide (1) a process for manufacturing alkali metal salts of 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole which are useful as gastric acid secretion inhibitors, anti-ulcer agents and other drugs and (2) salts of 2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole with amines which are intermediates for the production of the alkali metal salts, and a process for manufacturing the same. According to the present invention, disclosed are salts represented by the following formula (I): 
                         
(wherein A +  represents an isopropylammonium ion, sec-butylammonium ion or cyclopentylammonium ion).

TECHNICAL FIELD

The present invention relates to (1) a process for manufacturing alkalimetal salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewhich are useful as gastric acid secretion inhibitors, anti-ulcer agentsand other drugs and (2) salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines which are intermediates for the production of the alkalimetal salts, and a process for manufacturing them.

BACKGROUND ART

Alkali metal salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazoleare known to be useful as anti-ulcer agents and the like because theyhave the effect of inhibiting gastric acid secretion (see for exampleU.S. Pat. No. 5,045,552).

Although salts of the proton pump inhibitor omeprazole with amines areknown (see for example International Patent Publications (pamphlets) WO03/74514 and WO 94/27988 and European Patent Publication 124495), saltsof2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines are not known.

The crystallization process of salts of compounds such as omeprazolethat act as proton pump inhibitors with amines is also not known to beuseful for removing impurities and the like.

Moreover, no method is known of obtaining alkali metal salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolefrom salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines.

On the other hand, methods are known of manufacturing a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt in which the content of the impurity(2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(hereinafter simply referred to as “sulfone”) is reduced to between0.82% and 0.30% (see for example European Patent Publication 1000943).

DISCLOSURE OF THE INVENTION

When m-chloroperbenzoic acid or the like is used as an oxidizing agentin the final step of manufacturing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole,which is useful as an anti-ulcer agent, the sulfone,(2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole),may occur as an impurity.

Because it is difficult for this sulfone to be separated and purified,there is a demand for a new purification method capable of moreefficiently removing the sulfone and providing a better yield of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole.

The inventors of the present invention perfected the present inventionas a result of exhaustive research after discovering a purificationmethod for efficiently removing the sulfone which is the issue in thepreparation of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole,along with salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines that are useful in this purification method.

That is, in the first aspect of the present invention, there isprovided:

[1] a salt represented by the following formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion).

Moreover, in another aspect of the present invention, there areprovided:

[2] a salt represented by the following formula (II):

[3] a salt represented by the following formula (III):

and[4] a salt represented by the following formula (IV):

Moreover, in the second aspect of the present invention, there are

[5] a process for manufacturing salt comprising a salt-producing step,wherein the salt-producing step is accomplished in an ester solvent, anitrile solvent, an ether solvent, an alcohol solvent, a ketone solvent,an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, wateror a mixed solvent of the foregoing to produce the salt represented bythe following formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion), and[6] a process for manufacturing a salt comprising a salt-producing step,wherein the salt-producing step is accomplished in ethyl acetate,n-butyl acetate, diethyl carbonate, acetonitrile, t-butylmethyl ether,isopropanol, hexane, tetrahydrofuran, toluene or a mixed solvent of theforegoing to produce the salt represented by the following formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion).

Moreover, in the third aspect of the present invention, there areprovides:

[7] a process for manufacturing a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V), comprising reacting a salt represented by thefollowing formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion) with a base containing an alkali metal.[7-1] In a preferred aspect of the process for manufacturing (V) in thepresent invention, the reaction with the base containing an alkali metalis followed by crystallization, precipitation by salt-producing, orlyophilization in the manufacturing method described in the above [7].[7-2] In a preferred aspect of the process for manufacturing (V) in thepresent invention, an acetone complex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) is manufactured and then heat-dried in themanufacturing method described in the above [7].[7-3] In a preferred aspect of the process for manufacturing accordingto above [7-2], heat-drying is followed by crystallization,precipitation by salt-producing, or lyophilization.[7-4] In a preferred aspect of the process for manufacturing accordingto the above [7-2] or [7-3], the heat-drying temperature is from 30° C.to 130° C.[7-5] In a preferred aspect of the process for manufacturing accordingto the above [7-2] or [7-3], the heat-drying temperature is from 100° C.to 110° C.[7-6] In a preferred aspect of the process for manufacturing accordingto any of the above [7-2] to [7-5], heat-drying is performed under areduced pressure.

Moreover, in the fourth aspect of the present invention, there areprovides:

[8] a gastric acid secretion inhibitor comprising a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) and2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less,[8-1] a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) comprising a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) content of 0.2% or less (percentage based on combined weight ofcompounds (V) and (VI),[9] a therapeutic and/or preventive agent for a disorder caused bygastric acid, comprising a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) and2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less, and[10] the therapeutic and/or preventive agent according to the above [9],wherein the disorder caused by gastric acid is gastric ulcer, duodenalulcer, stomal ulcer, reflux esophagitis, Zollinger-Ellison syndrome,symptomatic reflux esophagitis, endoscopy negative reflux esophagitis,gastroesophageal reflux disease, laryngopharyngeal abnormalities,Barrett's esophagus, NSAID ulcer, gastritis, gastric bleeding,gastrointestinal bleeding, peptic ulcer, bleeding ulcer, stress ulcer,gastric hyperacidity, indigestion, gastric insufficiency, senile ulcer,intractable ulcer, acute gastric mucosal lesions, heartburn, toothgrinding, stomach pain, heavy stomach, temporomandibular arthrosis orgastric erosions.

[11] In a preferred aspect of the therapeutic and/or preventive agentaccording to the above [9] or [10], the disorder caused by gastric acidis gastric ulcer, duodenal ulcer, stomal ulcer, reflux esophagitis,Zollinger-Ellison syndrome or symptomatic reflux esophagitis.

[12] In a preferred aspect of the therapeutic and/or preventive agentaccording to any of the above [9] to [11], the disorder caused bygastric acid is reflux esophagitis or symptomatic reflux esophagitis.

[13] In a preferred aspect of the therapeutic and/or preventive agentaccording to any of the above [9] to [11], the disorder caused bygastric acid is gastric ulcer or duodenal ulcer.

Moreover, in still another aspect of the present invention, there areprovides:

[14] an antibacterial or antibacterial adjuvant against gastricHelicobacter pylori comprising a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) and2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less; and[15] a maintenance therapy agent for reflux esophagitis and/orsymptomatic reflux esophagitis comprising a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) and2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less.

In the term“2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) and2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less”, the term“2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less” means 0.2% or less based on thecombined weight of compound (V) and compound (VI).

In the above [8], [8-1], [9], [14] or [15], the content of compound (VI)based on the combined weight of compounds (V) and (VI) is 0.2% or less,preferably about 0.15% or less, more preferably about 0.15% to 0.01%,still more preferably about 0.1% to 0.01%.

ADVANTAGEOUS EFFECT OF THE INVENTION

According to the present invention, the sulfone contained as an impuritycan be efficiently removed by using salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines when manufacturing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole,which is useful as a drug.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the powder x-ray diffraction pattern of the salt obtainedin Example 1X-1 of the present invention;

FIG. 2 shows the powder x-ray diffraction pattern of the salt obtainedin Example 2X-1 of the present invention; and

FIG. 3 shows the powder x-ray diffraction pattern of the salt obtainedin Example 3X-1 of the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The following embodiments are illustrative to explain the presentinvention, and the present invention is not limited to only theseembodiments. The present invention can be carried out in various formsso long as the gist of the present invention is not deviated from.

The present invention provides salts for efficiently removing impuritiesproduced during the manufacture of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole,which is useful as a gastric acid secretion inhibitor, anti-ulcer agentor other drug, along with a process for manufacturing such salts.

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolerepresented by the formula (VII) is the compound represented by theformula (VIIa), the compound represented by the formula (VIIb) or amixture of compound (VIIa) and (VIIb) in any proportions, and ispreferably a 1:1 mixture of compounds (VIIa) and (VIIb):

The salt represented by the formula (I) in the present invention:

is a salt of compound (VII) with one amine selected from the groupconsisting of isopropylamine, sec-butylamine and cyclopentylamine, andis a salt formed by compound (VII) and the aforementioned amine in anyproportions. Preferably, it is a salt formed by compound (VII) and theaforementioned amine in proportions of approximately 1:1.

The salt represented by Formula (I) is not particularly limited as longas it is a salt formed by compound (VII) and one amine selected from thegroup consisting of isopropylamine, sec-butylamine and cyclopentylamine,but example aspects thereof include the salt represented by thefollowing the formula (VIII):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion), or the salt represented by the followingformula (IX):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion)

The term “ester solvent” used in the present invention refers to a C₃₋₇alkyl ester compound, and specific examples of the ester solvent includemethyl acetate, ethyl acetate, n-propyl acetate (acetic acid n-propylester), s-propyl acetate (acetic acid s-propyl ester), n-butyl acetate(acetic acid n-butyl ester), dimethyl carbonate, diethyl carbonate orthe like, with ethyl acetate, n-butyl acetate or the like beingpreferable examples.

The term “nitrile solvent” used in the present invention refers to aC₂₋₆ alkyl nitrile, and a specific example is acetonitrile.

The term “ether solvent” used in the present invention refers to adiC₁₋₆ alkyl ether or cyclic ether, and specific examples of the ethersolvent include dimethyl ether, t-butyl methyl ether tetrahydrofuran orthe like, with t-butyl methyl ether, tetrahydrofuran and the like beingpreferable examples.

The term “alcohol solvent” used in the present invention refers to aC₁₋₆ alkyl alcohol, and specific examples of the alcohol solvent includeethanol, isopropanol, n-propanol or the like, with isopropanol or thelike being preferable examples.

The term “ketone solvent” used in the present invention refers to adiC₁₋₆ alkyl ketone, and specific examples of the ketone solvent includedimethyl ketone, methyl ethyl ketone or the like.

The term “aliphatic hydrocarbon solvent” used in the present inventionrefers to a C₅₋₈ alkane, and specific examples of the aliphatichydrocarbon include hexane, heptane or the like, with hexane or the likebeing preferable example.

The term “aromatic hydrocarbon solvent” used in the present inventionrefers to a benzene which may have a substitutional group (C₁₋₆ alkylgroup, C₁₋₆ alkoxy group, nitrile group, halogen group or the like), andspecific examples of the aromatic hydrocarbon solvent include toluene,xylene, benzene or the like, with toluene or the like being preferableexample.

The term “alkali metal salt” used in the present invention is notparticularly limited as long as it is a salt with an alkali metal, butspecific examples of the alkali metal salt include sodium salts,potassium salts or the like, with sodium salts or the like beingpreferable example.

The term “base containing an alkali metal” used in the present inventionis not particularly limited as long as it is a base containing an alkalimetal such as sodium, potassium or the like, but specific examples ofthe base containing the alkali metal include sodium hydroxide, sodiumethoxide, sodium methoxide, sodium hydride, potassium hydroxide,potassium ethoxide, potassium methoxide, potassium hydride and solutionsof the foregoing, as well as ion exchange resins for converting toalkali metal salts, with sodium hydroxide or a sodium hydroxide solutionbeing preferable examples, and sodium hydroxide or a sodium hydroxideaqueous solution, sodium hydroxide methanol solution or sodium hydroxideethanol solution being more preferable examples.

The term “acetone complex of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt” used in the present invention is not particularlylimited as long as it is crystals of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt containing acetone, but specifically it may be theacetone complex of the2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt described in International Publication Pamphlet WO04/085424 or European Patent Publication 1000943.

The term “disorder caused by gastric acid” used in the present inventionis not particularly limited as long as it is a disorder caused bysecretion of gastric acid, but specific examples of the disorder causedby gastric acid include gastric ulcer, duodenal ulcer, stomal ulcer,reflux esophagitis, Zollinger-Ellison syndrome, symptomatic refluxesophagitis, endoscopy negative reflux esophagitis, gastroesophagealreflux disease, laryngopharyngeal abnormalities, Barrett's esophagus,NSAID ulcer, gastritis, gastric bleeding, gastrointestinal bleeding,peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperacidity,indigestion, gastric insufficiency, senile ulcer, intractable ulcer,acute gastric mucosal lesions, heartburn, tooth grinding, stomach pain,heavy stomach, temporbmandibular arthrosis and gastric erosions, withgastric ulcer, duodenal ulcer, stomal ulcer, reflux esophagitis,Zollinger-Ellison syndrome or symptomatic reflux esophagitis beingpreferred, reflux esophagitis, symptomatic reflux esophagitis, gastriculcer or duodenal ulcer being more preferable examples, and (1) refluxesophagitis or symptomatic reflux esophagitis or (2) gastric ulcer orduodenal ulcer being most preferable examples.

The present invention also provides an antibacterial agent orantibacterial adjuvant against Helicobacter pylori containing the saltrepresented by the above formula (I) or a solvate thereof. The term“preventive agent” may be an agent that is administered beforeoccurrence of a disorder, or one administered after healing for purposesof maintenance therapy or to prevent recurrence. The aforementioned“antibacterial adjuvant” is an agent that prepares the environment so asto allow the functioning of an antibacterial agent that does notfunction well under the acidic conditions.

The gastric acid secretion inhibitor and therapeutic and/or preventiveagent for the disorders caused by gastric acid of the present inventioncontains the2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt (V) and2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole(VI) in an amount of 0.2% or less, and may be mixed as necessary withknown pharmaceutically acceptable carriers (for example, excipients,binders, disintegrators, lubricants, colorants, flavorings, stabilizers,emulsifiers, absorbefacients, surfactants, pH adjusters, preservatives,antioxidants, etc.) and other components commonly used as raw materialsin the drug preparations, and prepared by ordinary methods. Thepreparation may be in a tablet, a powder, a granule, a grain, capsule, asyrup, a suppository or an injection form or the like.

There are no particular limitations on the mode of administration of thegastric acid secretion inhibitor and therapeutic and/or preventive agentfor the disorders caused by gastric acid of the present invention, whichis preferably administered orally or parenterally. The dosage of thegastric acid secretion inhibitor and therapeutic and/or preventive agentfor the disorders caused by gastric acid of the present invention isfrom 1 to 500 mg/day or preferably from 1 to 200 mg/day or morepreferably from 5 to 135 mg/day, depending on symptoms, age and thelike.

General Manufacturing Processes Manufacturing Process A Process formanufacturing salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines

The compound(2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole)(VII) used as the starting material in the manufacturing processaccording to the present invention can be manufactured by the processdescribed in U.S. Pat. No. 5,045,552 or by the known improvement on thisprocess (for example, Japanese Patent Applications Laid-open Nos.H11-71370 & 2000-143659, International Patent Publication (pamphlet) WO01/68594, European Patent Publication 1,270,555, etc.). The compound(VII) used as the starting raw material may either include or notinclude the sulfone,(2-[(4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazole)(VI).

An organic solvent and an amine (isopropylamine, sec-butylamine orcyclopentylamine) are added to dissolve2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(with heating if desired). This solution is then stirred at 30 to −40°C. (preferably −20 to −40° C.). The stirring time is not particularlylimited but is preferably from 1 hour to 1 day or more preferablyovernight (from 10 to 12 hours). Crystals are deposited in a step ofcooling and stirring.

Seed crystals (a small amount of crystals of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith an amine) may be added or not added during this crystal depositionstep. The temperature for adding the seed crystals is not particularlyrestricted but is preferably 55° C. or less or more preferably from 35°C. to 0° C. A solvent such as hexane, acetic acid n-butyl ester ort-butyl methyl ether can be added as appropriate before crystaldeposition or during step of crystal deposition.

Crystals deposited in the mixture can be filtered out to obtain thetarget salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith the amine.

The resulting crystals can be washed as necessary in the same solventused for dissolution. The resulting crystals can then be dried asnecessary at room temperature or with heating, either at a normalpressure or under a reduced pressure.

There are no particular limitations on the aforementioned organicsolvent, but specific examples of the organic solvent include estersolvents, nitrile solvents, ether solvents, alcohol solvents, ketonesolvents, aliphatic hydrocarbon solvents, aromatic hydrocarbon solvents,water and mixed solvents of the foregoing, and one or more solventsselected from the group consisting of ethyl acetate, n-butyl acetate,diethyl carbonate, tetrahydrofuran, acetonitrile, t-butyl methyl ether,hexane, isopropanol and toluene is preferred. The amount of the organicsolvent used is selected appropriately taking the smallest amount atwhich compound (VII) is dissolved by heating as the lower limit and thelargest amount at which the crystal yield does not decline dramaticallyas the upper limit, but preferably 3 to 30 times by volume of the weightof compound (VII) (v/w) or more preferably 5 to 20 times by volume ofthe weight of compound (VII) (v/w) is used.

The amount of amine used is not particularly limited as long as it is atleast equivalent to the amount of compound (VII), but it is preferablyfrom 1 to 10 times the molar amount of compound (VII) or more preferablyfrom 5 to 10 times the molar amount of compound (VII) or still morepreferably about 7 times the molar amount of compound (VII).

Manufacturing Process B Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt from salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amine

This step can be accomplished by the ordinary methods of convertingamine salts of organic compounds into alkali metal salts thereof.Specifically, a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith an amine is dissolved in 1 to 3 solvents selected from the groupconsisting of toluene, methanol, ethanol, water, acetone, ethyl acetate,acetonitrile, t-butyl methyl ether, tetrahydrofuran, hexane andisopropanol, and about 1 equivalent of a base (sodium hydroxide, sodiumethoxide, sodium methoxide, sodium hydride, potassium hydroxide,potassium ethoxide, potassium methoxide, potassium hydride or a solutionof the foregoing or the like) is added to the mixture and stirred. The2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt can be obtained by evaporating the solvent from thismixture.

This alkali metal salt can be obtained by crystallization, sedimentationby salt-producing or lyophilization from the mixture or a concentratedresidue thereof. This alkali metal salt can also be manufactured by asuitable combination of a step of manufacturing acetone-containingcrystals (an acetone complex) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazoleand a high-temperature drying step (International Publication PamphletWO 04/085424, European Patent Publication 1000943).

The resulting2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolealkali metal salt can also be dried at 30° C. to 60° C. under a reducedpressure or at a normal pressure. This drying step can be performedeither statically or with shaking, under ventilation if desired.

Manufacturing Process C Manufacturing step of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole

The compound (VII) used as the starting raw material in themanufacturing process according to the present invention can bemanufactured by the methods shown below.

The compound represented by the formula (3×) above (hereinafter simplyreferred to as “compound (3x)”; the same applies to the compoundsrepresented by the formulae (4x) and (5x)) through compound (5) are allknown compounds.

(Step 1x)

This step is a step wherein the crude compound (4x) is manufactured byreacting compound (3x) with a chlorinating agent in an inactive solventand concentrating the resulting reaction mixture. The inactive solventused in this step is not particularly limited as long as it can dissolvethe raw material compounds somewhat without impeding the reaction.Preferable examples of the inactive solvent used in this step includearomatic hydrocarbons such as benzene, toluene or xylene, organic acidesters such as methyl acetate or ethyl acetate, ethers such as diethylether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane,halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride or dichloroethane, or the like. It is especiallypreferable to use toluene, ethyl acetate, dimethoxyethane ordichloromethane.

Examples of the chlorinating agent used in this step include phosphorustrichloride, phosphorus pentachloride, phosphorus oxychloride, thionylchloride or the like can be used as the chlorinating agent in this step,but preferably one is used such as thionyl chloride that can beevaporated together with the solvent.

The reaction temperature for this step varies depending on the solvents,the raw material compounds and the chlorinating agents used or the like,but is generally from −20° C. to 50° C. or preferably from 0 to 30° C.The reaction time for this step varies depending on the solvents, theraw material compounds, the chlorinating agents, reaction temperature orthe like, but is generally from 30 minutes to 6 hours or preferably from1 to 2 hours.

After completion of the reaction, (1) quenching, (2) concentration anddrying of the reaction mixture and (3) purification, etc. are performedas appropriate. To quench the reaction, for example a suitable amount ofwater or a lower alcohol (particularly ethanol) can be added to thereaction mixture.

After quenching and concentration and drying of the reaction mixture,the reaction mixture can be used as is in Step 2x without any particularpurification, and preferably it is used as is after quenching with onlyslight concentration and drying and purification.

(Step 2x)

This step is a step wherein compound (5x) is manufactured by reacting

2-benzimidazole thiol with compound (4x) obtained in Step 1 in thepresence of a base. The inactive solvent used in this step is notparticularly limited as long as it can dissolve the raw materialcompounds somewhat without impeding the reaction, but for example, it ispreferable to use alcohols such as methanol, ethanol, propanol,isopropanol, butanol or tert-butanol, aromatic hydrocarbons such asbenzene, toluene or xylene or a mixed solvent of the foregoing.

The base used in this step is not particularly limited as long as itdissolves to a certain extent in the solvent. Examples of the baseinclude alkali metal hydrides such as sodium hydroxide or potassiumhydroxide, and sodium hydroxide is preferred. The reaction temperaturefor this step varies depending on the solvent, the raw materialcompounds and the base used or the like, but is generally from −20° C.to 70° C. or preferably from 20 to 70° C.

The reaction time for this step varies depending on the solvent, the rawmaterial compounds, the base, the reaction temperature or the like, butis generally from 30 minutes to 6 hours, preferably from 1 to 2 hours.

After completion of the reaction, compound (5x) can be separated fromthe reaction mixture by the standard methods. For example, aftercompletion of the reaction the reaction mixture can be concentratedunder a reduced pressure and then extracted with water and an organicsolvent not miscible with water (such as dichloromethane, ethyl acetate,methyl acetate, n-butyl acetate or toluene), and the organic layer canthen be washed with aqueous sodium hydroxide solution and water andconcentrated to manufacture compound (5x). After completion of thereaction the reaction mixture can also be washed with water and used inStep 3x without any concentration or purification.

In particular, a highly pure compound (5x) can be manufactured as acrystal using an organic solvent such as the following:

ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane or dimethoxyethane (particularly diisopropylether or t-butyl methyl ether);

nitriles such as acetonitrile (particularly acetonitrile);

aromatic hydrocarbons such as benzene, toluene or xylene (particularlytoluene);

alcohols such as methanol, ethanol, propanol or isopropanol(particularly isopropanol);

ketones such as acetone or methyl ethyl ketone (particularly acetone);

organic acid esters such as methyl acetate, ethyl acetate, dimethylcarbonate or diethyl carbonate (particularly ethyl acetate or diethylacetate); or

a mixed solvent containing at least two of these solvents.

The amount of solvent used during crystallization varies according tothe type of solvent, but is from 3 to 40 ml based on 1 g of compound(5).

(Step 3x)

This step is a step wherein compound (1) is manufacturing by reactingcompound (5x) with an oxidizing agent in an inactive solvent. Theinactive solvent used in this step is not particularly limited as longas it can dissolve the raw material compounds somewhat without impedingthe reaction. Preferable examples of the inactive solvent includehalogenated hydrocarbons such as chloroform, dichloromethane, carbontetrachloride or dichloroethane, aromatic hydrocarbons such as benzene,toluene or xylene, alcohols such as methanol, ethanol, propanol,isopropanol, butanol or tert-butanol, or a mixed solvent of theforegoing, with dichloromethane, toluene, methanol, ethanol or a mixedsolvent of the foregoing being particularly preferable.

Examples of the oxidizing agent used in this step include hydrogenperoxide, peracetic acid, m-chloroperbenzoic acid, sodium periodate orthe like, m-chloroperbenzoic acid being preferably used, in an amount offrom 0.3 to 1.1 equivalents based on compound (5×).

The reaction temperature for this step varies depending on the solvent,raw material compounds and the oxidizing agent used or the like, but isgenerally from −50° C. to 0° C., preferably from −40° C. to −10° C. Thereaction time for this step varies depending on the solvent, the rawmaterial compounds, the oxidizing agent, reaction temperature or thelike, but is generally from 30 minutes to 6 hours, preferably from 1 to2 hours.

After completion of the reaction, compound (1) can be separated from thereaction mixture by the standard methods, for example by performing thefollowing operations in sequence:

(Operation 1): a basic aqueous solution (such as an aqueous solution ofan alkali metal hydroxide, particularly an aqueous sodium hydroxidesolution) is added to the resulting reaction mixture, followed byvigorous stirring or shaking and then standing, and the organic layer isseparated to obtain water layer (a);

(Operation 2): an organic solvent (for example, a halogenatedhydrocarbon such as chloroform, dichloromethane, carbon tetrachloride ordichloroethane, an organic acid ester such as ethyl acetate, methylacetate or n-butyl acetate, an aromatic hydrocarbon such as toluene, analcohol including butanol and mixtures of these) is added to water layer(a), followed by vigorous stirring or shaking and then standing, and theorganic layer is separated to obtain water layer (b);

(Operation 3): the same organic solvent is added to water layer (b),which is then vigorously stirring or shaking and then allowed to standin a state of a pH of 8.0 to 11.0, and separated to obtain organic layer(a) and water layer (c) (an aqueous buffer solution such as an aqueousammonium acetate solution or acetic acid can be added here asappropriate);

(Operation 4): the same organic solvent is added to water layer (c),followed by vigorous stirring or shaking and then standing, organiclayer (b) is separated and combined with organic layer (a), and water orsodium bicarbonate solution is added to the mixture followed by vigorousstirring or shaking and then standing, after which the water layer isremoved and the resulting organic layer (c) is concentrated.

In particular, a highly pure compound (I) can be manufactured as thecrystals by crystallization using an organic solvent such as thefollowing after concentration:

ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether,tetrahydrofuran, dioxane or dimethoxyethane (particularly diethylether);

nitriles such as acetonitrile (particularly acetonitrile);

aromatic hydrocarbons such as benzene, toluene or xylene (particularlytoluene);

alcohols such as methanol, ethanol, propanol, isopropanol or isobutylalcohol (particularly isopropanol);

ketones such as acetone or methyl ethyl ketone (particularly acetone);

organic acid esters such as methyl acetate, ethyl acetate, n-butylacetate, dimethyl carbonate or diethyl carbonate (particularly n-butylacetate); or

a mixture of these solvents (particularly a mixture of a nitrile with anorganic acid ester).

The water layer (a) obtained by the above Operation 1 or the water layer(b) obtained by the above Operations 1 and 2 can also be used inmanufacturing process A without any concentration or purification.

The present invention will be explained in more detail below usingexamples and reference examples. However, these are only illustrativeand the present invention is not in any way limited thereto.

The term “sulfone (VI)” used in the present invention means(2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfonyl]-1H-benzimidazolerepresented by the following formula:

The abbreviations used below are defined as follows:

mcpba: meta-chloroperbenzoic acid

TLC: thin-layer chromatography

HPLC: high-performance liquid chromatograph.

EXAMPLES Synthesis of2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine Reference Example 1

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in toluene (40 ml), and thionyl chloride (4.23 g(35.6 mmol)) was added dropwise thereto so that the temperature did notexceed 25° C. Following stirring at room temperature, disappearance ofthe raw materials was confirmed by TLC, and2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.13 g) wasobtained by concentrating under a reduced pressure (yield: 97.3%).

Reference Example 2

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride(4.23 g. (35.6 mmol)) was added dropwise thereto so that the temperaturedid not exceed 25° C. Following stirring at room temperature,disappearance of the raw materials was confirmed by TLC, and2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.14 g) wasobtained by concentrating under a reduced pressure (yield: 97.4%).

Reference Example 3

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in dimethoxyethane (40 ml), and thionyl chloride(4.23 g (35.6 mmol)) was added dropwise thereto so that the temperaturedid not exceed 25° C. Following stirring at room temperature,disappearance of the raw materials was confirmed by TLC, and2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.25 g) wasobtained by concentrating under a reduced pressure (yield: 99.2%).

Reference Example 4

2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7mmol)) was dissolved in dichloromethane (40 ml), and thionyl chloride(4.23 g (35.6 mmol)) was added dropwise thereto so that the temperaturedid not exceed 25° C. Following stirring at room temperature,disappearance of the raw materials was confirmed by TLC, and2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.23 g) wasobtained by concentrating under a reduced pressure (yield: 99.0%).

Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazoleReference Example 5-1

2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (53.2 g (200mmol)), denatured ethanol (320 ml), 2-benzimidazole thiol (30.2 g (201mmol)) and sodium hydroxide (26.8 g (670 mmol)) were added together andreacted for about 2 hours at 50° C. After disappearance of the rawmaterials had been confirmed by TLC, this solution was concentratedunder a reduced pressure and ethyl acetate (430 ml) and water (340 ml)were added thereto, followed by stirring and standing, and the waterlayer was then separated. The organic layer was washed with 10% aqueoussodium hydroxide solution (110 ml) and water (2×110 ml) and concentratedunder a reduced pressure to obtain crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(69.0 g) (HPLC purity 98.7%, yield 101%).

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) was crystallized with ethyl acetate (25 ml) and filtered toobtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.80 g) (HPLC purity 99.2%, yield 96:0%).

Reference Example 5-2

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized withtert-butyl(methyl)ether (30 m), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.50 g) (HPLC purity 99.2%), yield 90.0%).

Reference Example 5-3

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized withdiisopropyl ether (200 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.94 g) (HPLC purity 99.1%, yield 98.8%).

Reference Example 5-4

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized with toluene(30 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.56 g) (HPLC purity 99.1%, yield 91.2%).

Reference Example 5-5

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized withacetonitrile (40 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.64 g) (HPLC purity 99.1%, yield 92.8%).

Reference Example 5-6

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized withisopropyl alcohol (20 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.55 g) (HPLC purity 99.1%, yield 91.0%).

Reference Example 5-7

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized with acetone(20 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.80 g) (HPLC purity 99.2%, yield 96.0%).

Reference Example 5-8

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(5.00 g) obtained in Reference Example 5-1 was crystallized with diethylcarbonate (90 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(4.85 g) (HPLC purity 99.2%, yield 97.0%).

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole-producingstep Reference Example 6-1

2-Chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (26.6 g (100mmol)), denatured ethanol (160 ml), 2-benzimidazole thiol (15.0 g (100mmol)) and sodium hydroxide (13.4 g (335 mmol)) were added together andreacted for about 2 hours at 50° C. After disappearance of the rawmaterials had been confirmed by TLC, this solution was concentratedunder a reduced pressure, toluene (30 ml) and water (168 ml) were addedthereto. After stirring and still standing the water layer wasseparated. The organic layer was washed with 10% aqueous sodiumhydroxide solution (50 ml) and water (2×50 ml) and concentrated under areduced pressure to obtain crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(34.8 g) (HPLC purity 98.7%, yield 101%).

Reference Example 6-2

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized with ethylacetate (12 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.91 g) (HPLC purity 99.3%, yield 97.0%).

Reference Example 6-3

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized withtert-butyl(methyl)ether (12 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.79 g) (HPLC purity 99.2%, yield 93.0%).

Reference Example 6-4

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized with toluene(15 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.84 g) (HPLC purity 99.1%, yield 94.5%).

Reference Example 6-5

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized withacetonitrile (21 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.81 g) (HPLC purity 99.1%, yield 93.5%).

Reference Example 6-6

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized withdiisopropyl alcohol (9 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.78 g) (HPLC purity 99.4%, yield 92.5%).

Reference Example 6-7

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized with acetone(9 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.91 g) (HPLC purity 99.3%, yield 97.0%).

Reference Example 6-8

The crude2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(3.00 g) obtained in Reference Example 6-1 was crystallized with diethylcarbonate (45 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(2.93 g) (HPLC purity 99.3%, yield 97.5%).

HPLC purity in Reference Examples 5-1 through 6-8 was measured under thefollowing conditions.

HPLC Conditions

Column: Inertsil ODS-2 (GL Sciences) Mobile phase:Acetonitrile:water:ammonium acetate = 500:500:1 Flow rate:  0.7 ml/minColumn temperature: 35° C. Detector: 258 nm

Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazoleReference Example 7

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 5.37 g (21.8 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized withdichloromethane (14 ml) and acetonitrile (92 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(6.26 g) (HPLC purity 99.7%, yield 23.9%).

Reference Example 8

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 5.37 g (21.8 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized with ethylacetate (66 ml) and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(6.15 g) (HPLC purity 99.8%, yield 23.5%).

Reference Example 9

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 7.16 g (29.1 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed twice with water (48ml), concentrated under a reduced pressure, crystallized withdichloromethane (18 ml) and acetone (120 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(8.56 g) (HPLC purity 99.7%, yield 32.7%).

Reference Example 10

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 7.16 g (29.1 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized withisopropyl alcohol (88 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(8.29 g) (HPLC purity 99.7%, yield 31.7%).

Reference Example 11

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 7.16 g (29.1 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized withacetonitrile (132 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(8.25 g) (HPLC purity 99.7%, yield 31.5%).

Reference Example 12

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 8.95 g (36.4 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized with acetone(165 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(10.8 g) (HPLC purity 99.6%, yield 41.4%).

Reference Example 13

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 8.95 g (36.4 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized with toluene(110 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(10.6 g) (HPLC purity 99.6%, yield 40.4%).

Reference Example 14

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 8.95 g (36.4 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized withdichloromethane (28 ml) and ethyl acetate (184 ml), and filtered toobtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(10.9 g) (HPLC purity 99.7%, yield 41.7%).

Reference Example 15

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 10.7 g (43.7 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized with acetone(198 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(12.6 g) (HPLC purity 99.3%, yield 48.3%).

Reference Example 16

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole(25.0 g (72.8 mmol)) was dissolved in dichloromethane and cooled. Then,mcpba (70.2% purity; 10.7 g (43.7 mmol)) was added gradually so that theinternal temperature did not exceed −15° C. 10% Aqueous sodium hydroxidesolution (70.8 ml) was then added, and after stirring and still standingthe water layer was separated. The separated water layer was washed withdichloromethane (48 ml) twice. After addition of a 2N-ammonium acetateaqueous solution, the water layer was extracted with dichloromethane (48ml) twice. The dichloromethane layer was washed with water (48 ml)twice, concentrated under a reduced pressure, crystallized withdichloromethane (27 ml) and ether (220 ml), and filtered to obtain2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(14.5 g) (HPLC purity 99.1%, yield 55.4%).

Reference Example 17

To a mixed solution of2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (12.02 g (56.9mmol)) and toluene (96.0 ml) was added dropwise thionyl chloride (8.11 g(68.2 mmol)), so that the internal temperature did not exceed 25° C.,which was stirred for about 90 minutes at room temperature. Ethanol(24.0 ml) was added to this mixed solution to obtain a2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine solution.

To this 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridin solution wasadded 2-benzimidazole thiol (8.71 g (58.0 mmol)) at room temperature. A25% aqueous sodium hydroxide solution (40.6 g) was added gradually asthe temperature (internal temperature) was gradually raised to 65° C.The reaction mixture was stirred for about an hour and a half at 65° C.(internal temperature). Water (60.0 ml) was added to the reactionmixture at 65° C., after which 25% aqueous sodium hydroxide solution(0.2 g) was added and stirred. This reaction mixture was allowed tostand, and the water layer was separated. The organic layer was washedwith water (20.0 ml) twice, and toluene (79.6 ml) and methanol (21.5 ml)were added to the organic layer to obtain a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazolesolution.

This2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H-benzimidazolesolution was cooled to 30° C. (external temperature), and a solution ofmcpba (70.2% purity; 14.39 g (58.5 mmol)), methanol (12.4 ml) andtoluene (10.5 ml) were added over the course of about 1 hour so as notto exceed an internal temperature of −25° C., and then stirred for anhour- and a half. 25% Aqueous sodium hydroxide solution (22.73 g) andwater (17.6 ml) were added to the reaction mixture and stirred. Thisreaction mixture was allowed to stand, and the organic layer wasseparated to obtain an aqueous alkali solution containing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole.

HPLC purity in Reference Examples 7 through 16 was measured under thefollowing conditions.

HPLC Conditions

Column: Nucleosil 5cl8 (Chemco) Mobile phase: Methanol:Phosphoric acidbuffer (pH 7) = 3:2) Flow rate:  1.0 ml/min Detector: 290 nm

The compounds (VII) used as the starting raw materials in Examples 1-1through 3-1 were compounds containing 1.61%, 1.44%, 0.57%, 0.56% and0.45% of the sulfone (VI) which can be manufactured by the methoddescribed in U.S. Pat. No. 5,045,552 or by the known improvement on thismethod (for example, Japanese Patent Applications Laid-open Nos.H11-71370 & 2000-143659, International Patent Publication Pamphlet WO01/68594, European Patent Publication 1,270,555, etc.).

Example 1-1 Synthesis of a salt of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

To2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 1.44%) was added acetonitrile(30 ml), which was dissolved at 55° C. (external temperature), andisopropylamine (4.97 ml, 58.4 mmol) was then added. This mixture wascooled at 30° C. (external temperature), hexane (15 ml) and a traceamount of seed crystals (crystals of salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine) were added and stirred for about 2 hours. Thismixture was then cooled at −25° C. (external temperature), and stirredovernight. The crystals deposited in the mixture were filtered, washedwith acetonitrile (10 ml) cooled at −30° C., and dried under a reducedpressure at room temperature to obtain white crystals of the titledcompound (3.30 g; 7.88 mmol, yield 94.5%, sulfone (VI) content 0.02%).

¹H-NMR (400 MHz, CDCL₃) δ:1.08 (d, J=6.3 Hz, 6H), 2.08 (tt, J=6.1, 6.1Hz, 2H), 2.20 (s, 3H), 2.84 (brs 3H), 3.11 (sept, J=6.3 Hz, 1H), 3.36(s, 3H), 3.55 (t, J=6.1 Hz, 2H), 4.11 (t, J=6.1 Hz, 2H), 4.65 (d, J=13.7Hz, 1H), 4.83 (d, J=13.7 Hz, 1H), 6.75 (d, J=5.9 Hz, 1H), 7.33 (dd,J=3.2, 6.1 Hz, 2H), 7.66 (dd, J=3.2, 6.1 Hz, 2H), 8.31 (d, J=5.9 Hz,1H).

Note that the sulfone (VI) content was measured by HPLC(high-performance liquid chromatography) under the following conditions.

HPLC Analysis Conditions:

Column: YMC-Pack Pro C18 AS-303 250 mm × 4.6 mm I.D. Mobile phase:MeOH/H₂O/AcONH₄ = 550 mL/450 mL/2 g Flow rate: 1.0 mL/min Detection: UV290 nm, column temp. 35° C.

Example 1-2 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

To2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.56%) was added ethyl acetate(45 ml), which was dissolved at 55° C. (external temperature), andisopropylamine (4.97 ml, 58.4 mmol) was then added. This mixture wascooled, and stirred for about 7 hours at room temperature. The crystalsdeposited in the mixture were filtered, washed with ethyl acetate (20ml) and dried under a reduced pressure at room temperature to obtainwhite crystals of the title compound (2.63 g; 6.28 mmol, yield 75.3%,sulfone (VI) content 0.17%).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 1-3 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.57%) as the raw material,ethyl acetate (45 ml) was replaced by tetrahydrofuran (15 ml) as thesolvent, and ethyl acetate (20 ml) was replaced by tetrahydrofuran (10ml) for washing the crystals.

White crystals of the title compound (2.64 g; 6.31 mmol, yield 75.6%,sulfone (VI) content 0.02% or less) were then obtained by methodssimilar to those used in Example 1-2, except for the solvent and thewashing solvent.

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 1-4 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 1.44%) as the raw material,ethyl acetate (45 ml) was replaced by acetonitrile (30 ml) as thesolvent, and overnight stirring after addition of the amine wasperformed at 0° C. (external temperature).

White crystals of the title compound (2.90 g; 6.93 mmol, yield 83.0%,sulfone (VI) content 0.02% or less) were then obtained by methodssimilar to those used in Example 1-2, except for the solvent and thestirring conditions.

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 1-5 Synthesis of a salt of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 1.44%) as the raw material,t-butyl methyl ether (9 ml) was used in place of hexane (15 ml), andovernight stirring after addition of the amine was performed at 0° C.(external temperature).

White crystals of the title compound (2.89 g; 6.91 mmol, yield 82.7%,sulfone (VI) content 0.02% or less) was then obtained by methods similarto those used in Example 1-1, except for the solvent and the stirringconditions

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1-1, and the sulfone (VI) content was confirmed underthe same conditions as in Example 1-1.

Example 1-6 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 1.44%) as the raw material,overnight stirring after addition of the amine was performed at 0° C.(external temperature), and the same methods were used as in Example1-1, except for the stirring conditions, to obtain white crystals of thetitle compound (3.17 g; 7.57 mmol, yield 90.6%, sulfone (VI) content0.02% or less).

Example 1-7 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.01 g, 8.37 mmol, sulfone (VI) content 1.44%) as the raw material, theamount of isopropylamine was changed from (4.97 ml, 58.4 mmol) to (2.13ml, 25.0 mmol).

The amount of hexane was also changed from 15 ml to 9 ml. Overnightstirring after addition of the amine was performed at 0° C. (externaltemperature), and the same methods were used as in Example 1-1, exceptfor the amounts of the solvent and the amine, to obtain white crystalsof the title compound (3.16 g; 7.55 mmol, yield 90.2%, sulfone (VI)content 0.03% or less).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 1-8 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 1.44%) was dissolved inacetonitrile (28.1 ml) and isopropylamine (5.0 ml) at 30° C. Then,acetic acid n-butyl ester (23.0 ml) and a trace amount of seed crystals(crystals of salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine) were added, stirred for 1 hour, cooled to −25° C.and then stirred overnight. The deposited crystals were filtered, washedwith acetonitrile (5 ml) chilled at −25° C. (external temperature), anddried under a reduced pressure at room temperature to obtain whitecrystals of the title compound (3.46 g; yield 93.7%, sulfone (VI)content 0.02% or less). The sulfone content was confirmed under the sameconditions as in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.08 (d, J=6.3 Hz, 6H), 2.07 (tt, J=6.1, 6.1Hz, 2H), 2.18 (s, 3H), 3.11 (sept, J=6.3 Hz, 1H), 3.35 (s, 3H), 3.54 (t,J=6.1 Hz, 2H), 4.09 (t, J=6.1 Hz, 2H), 4.66 (d, J=13.7 Hz, 1H), 4.82 (d,J=13.7 Hz, 1H), 6.73 (d, J=5.6 Hz, 1H), 7.30-7.34 (m, 2H), 7.62-7.67 (m,2H), 8.30 (d, J=5.6 Hz, 1H).

Example 2-1 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine

To2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.57%) was added toluene (60ml), which was dissolved at 55° C., and cyclopentylamine (5.76 ml, 58.4mmol) was then added. This mixture was cooled at −10° C. (externaltemperature), and stirred overnight.

The crystals deposited in the mixture were filtered, washed with toluene(10 ml) chilled at −30° C., and dried under a reduced pressure at roomtemperature to obtain white crystals of the title compound (2.97 g; 6.68mmol, yield 80.0%, sulfone (VI) content 0.06%). The sulfone content wasconfirmed under the same conditions as in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.23-1.33 (m, 2H), 1.51-1.58 (m, 2H),1.66-1.75 (m, 2H), 1.80-1.87 (m, 2H), 2.06 (tt, J=6.1, 6.1 Hz, 2H), 2.17(s, 3H), 3.30-3.38 (m, 1H), 3.35 (s, 3H), 3.49 (brs 3H), 3.53 (t, J=6.1Hz, 2H), 4.08 (t, J=6.1 Hz, 2H), 4.70 (d, J=13.7 Hz, 1H), 4.81 (d,J=13.7 Hz, 1H), 6.72 (d, J=5.6 Hz, 1H), 7.31 (dd, J=3.2, 6.1 Hz, 2H),7.63 (dd, J=3.2, 6.1 Hz, 2H), 8.29 (d, J=5.6 Hz, 1H).

Example 2-2 Synthesis of a salt of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.01 g, 8.37 mmol, sulfone (VI) content 0.57%) as the raw material,toluene (60 ml) was replaced by ethyl acetate (45 ml) as the solvent,and overnight stirring after addition of the amine was performed at −40°C. (external temperature).

The same methods were used as in Example 2-1, except for the solvent andthe stirring conditions, to obtain white crystals of the title compound(3.21 g; 7.22 mmol, yield 86.4%, sulfone (VI) content 0.26%).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 2-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 2-3 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine

Using2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.57%) as the raw material,toluene (60 ml) was replaced by isopropanol (21 ml) as the solvent, andovernight stirring after addition of the amine was performed at −40° C.(external temperature).

The same methods were used as in Example 2-1, except for the solvent andthe stirring conditions, to obtain white crystals of the title compound(3.30 g (7.42 mmol, yield 88.9%, sulfone (VI) content 0.26%).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 2-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 2-4 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine

2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.45%) as the raw material wasdissolved in acetonitrile (28.1 ml) and cyclopentylamine (5.7 ml). Afteraddition of acetic acid n-butyl ester (23.0 ml), this mixture was cooledto 10° C. and a trace amount of seed crystals (crystals of salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine) were added followed by stirring for 1 hour,cooling to −25° C., and overnight stirring was performed. The depositedcrystals were filtered, washed with acetonitrile (5 ml) chilled at −25°C. (external temperature), and dried under a reduced pressure at roomtemperature to obtain white crystals of the title compound (3.35 g;yield 90.3%, sulfone (VI) content 0.06%).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 2-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 3-1 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine

To2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.57%) was added ethyl acetate(45 ml), which was dissolved at 55° C., and sec-butylamine (5.90 ml,58.4 mmol) was then added. This mixture was cooled at −40° C. (externaltemperature), and stirred overnight.

The crystals deposited in the mixture were filtered, washed with ethylacetate (10 ml) chilled at −30° C., and dried under a reduced pressureat room temperature to obtain white crystals of the title compound (3.14g; 7.26 mmol, yield 86.9%, sulfone (VI) content 0.02% or less). Thesulfone content was confirmed under the same conditions as in Example1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (d, J=7.4 Hz, 3H), 1.06 (d, J=6.3 Hz,3H), 1.31-1.39 (m, 2H), 2.07 (tt, J=6.1, 6.1 Hz, 2H), 2.19 (s, 3H), 2.80(brs 3H), 2.77-2.84 (m, 1H), 3.36 (s, 3H), 3.55 (t, J=6.1 Hz, 2H), 4.10(t, J=6.1 Hz, 2H), 4.66 (d, J=13.7 Hz, 1H), 4.82 (d, J=13.7 Hz, 1H),6.74 (d, J=5.6 Hz, 1H), 7.33 (dd, J=3.2, 6.1 Hz, 2H), 7.66 (dd, J=3.2,6.1 Hz, 2H), 8.31 (d, J=5.6 Hz, 1H).

Example 3-2 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 0.45%) was dissolved inacetonitrile (51.0 ml) and sec-butylamine (5.93 ml). Then, this mixturewas cooled to 15° C. and a trace amount of seed crystals (crystals ofsalt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine) were added followed by stirring for 1 hour, coolingto −25° C., and overnight stirring was performed. The deposited crystalswere filtered, washed (external temperature) with acetonitrile (5 ml)chilled at −25° C., and dried under a reduced pressure at roomtemperature to obtain white crystals of the title compound (3.15 g;yield 87.1%, sulfone (VI) content 0.02% or less).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 3-1, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 3-3 Synthesis of a salt of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(3.00 g, 8.35 mmol, sulfone (VI) content 1.61%) was dissolved inacetonitrile (28.1 ml) and sec-butylamine (5.9 ml). Then, diethylcarbonate (23.0 ml) was added, followed by cooling to 15° C., and atrace amount of seed crystals (crystals of salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine) were added followed by stirring for 1 hour, coolingto −25° C., and overnight stirring was performed. The deposited crystalswere filtered, washed with acetonitrile (5 ml) chilled at −25° C.(external temperature), and dried under a reduced pressure at roomtemperature to obtain white crystals of the title compound (3.23 g;yield 89.4%, sulfone (VI) content 0.02% or less).

The resulting salt was confirmed from the NMR data to be the same asthat obtained in Example 3-1, and the sulfone content was confirmedunder the same conditions as in Example 1-1.

An aqueous sodium hydroxide solution (extract obtained with aqueoussodium hydroxide solution after reaction) of compound (VII) obtained inthe above Reference Examples 7-17 or by methods similar to those ofJapanese Patent Application Laid-open H11-71.370 (Example 1) was usedfor the alkali solution of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewhich is the starting material in the following Examples 1X-1, 2X-1 and3X-1.

Example 1X-1 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine

To an alkali solution (41.77 g (sulfone (VI) content 1.75%)) containing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(7.37 g) were added water (64.4 ml), toluene (69.4 ml) and 1-butanol(3.7 ml), which was stirred. Then, acetic acid (1.74 g) was added toadjust a pH to 9.0. This mixture solution was separated into a toluenelayer and a water layer, and the water layer was further extracted withtoluene (54.0 ml), and combined with the previously extracted toluenelayer. The combined toluene layer was washed with water (15.4 ml), andconcentrated under a reduced pressure after addition of isopropylamine(5.7 ml). To the resulting residue were added acetonitrile (58.0 ml) andisopropylamine (1.9 ml), which was then concentrated again under areduced pressure. To the concentrated residue were added acetonitrile(62.3 ml) and isopropylamine (10.2 ml), which was stirred at 30° C.Acetic acid n-butyl ester (54.6 ml) and a trace amount of seed crystals(salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine) were added, and the mixture was then cooled to −25°C. (external temperature) and stirred overnight. The deposit wasfiltered, washed with acetonitrile (15 ml) chilled at −25° C. (externaltemperature), and dried under a reduced pressure for about 6 hours atroom temperature to obtain white crystals of the title compound (7.94 g;yield 92.5%, sulfone (VI) content 0.02% or less). The sulfone contentwas confirmed under the same conditions as in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.07 (d, J=6.1 Hz, 6H), 2.08 (tt, J=6.1, 6.1Hz, 2H), 2.20 (s, 3H), 3.11 (sept, J=6.1 Hz, 1H), 3.36 (s, 3H), 3.55 (t,J=6.1 Hz, 2H), 4.11 (t, J=6.1 Hz, 2H), 4.63 (d, J=13.7 Hz, 1H), 4.83 (d,J=13.7 Hz, 1H), 6.75 (d, J=5.6 Hz, 1H), 7.34 (dd, J=3.2, 6.2 Hz, 2H),7.67 (dd, J=3.2, 6.2 Hz, 2H), 8.32 (d, J=5.6 Hz, 1H).

Example 1X-2 Synthesis of an acetone complex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

To a salt (2.51 g; 60 mmol, sulfone (VI) content 0.02% or less) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine were added ethanol (26.1 ml) and ethyl acetate (26.1ml), which was dissolved at room temperature. To this solution was added5 mol/L aqueous sodium hydroxide solution (1.11 ml), which was thenconcentrated under a reduced pressure. To the residue were added ethylacetate (50.4 ml) and acetone (2.5 ml), which was concentrated againunder a reduced pressure. To the resulting solids were added ethylacetate (18.0 ml) and acetone (12.0 ml). To this mixture solution wasadded a trace amount of seed crystals (acetone complex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt), which was stirred overnight at room temperature. Thedeposit was filtered, washed with acetone (7 ml), and dried under areduced pressure at room temperature to obtain white crystals of thetitle compound (2.35 g; 5.3 mmol, yield 89.2%).

Example 1X-3 Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt (2.07 g; sulfone (VI) content 0.02% or less) was obtained bythe methods similar to those of WO2004-085424, Example 6 using anacetone complex (2.35 g) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt. The sulfone content was confirmed under the same conditionsas in Example 1-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.97 (tt, J=6.1, 6.1 Hz, 2H), 2.17 (s, 3H),3.24 (s, 3H), 3.48 (t, J=6.1 Hz, 2H), 4.09 (t, J=6.1 Hz, 2H), 4.39 (d,J=12.9 Hz, 1H), 4.74 (d, J=12.9 Hz, 1H), 6.85 (dd, J=3.2, 6.1 Hz, 2H),6.92 (d, J=5.6 Hz, 1H), 7.43 (dd, J=3.2, 6.1 Hz, 2H), 8.27 (d, J=5.6 Hz,1H).

Example 1X-4 Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

A salt (2.00 g; 4.8 mmol, sulfone (VI) content 0.02% or less) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine, water (5.0 ml) and 5 mol/L aqueous sodium hydroxidesolution (0.89 ml) were added together and dissolved by stirring, andthen washed with water (1.0 ml) and lyophilized. This was then driedunder a reduced pressure for about 21 hours at 50° C. to obtain a whitesolid of the title compound (1.79 g; 4.7 mmol, yield 98.0%, sulfone (VI)content 0.02% or less). The sulfone content was confirmed under the sameconditions as in Example 1-1.

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.97 (tt, J=6.1, 6.1 Hz, 2H), 2.17 (s, 3H),3.24 (s, 3H), 3.48 (t, J=6.1 Hz, 2H), 4.08 (t, J=6.1 Hz, 2H), 4.39 (d,J=12.7 Hz, 1H), 4.77 (d, J=12.7 Hz, 1H), 6.86 (dd, J=3.2, 6.1 Hz, 2H),6.91 (d, J=5.6 Hz, 1H), 7.44 (dd, J=3.2, 6.1 Hz, 2H), 8.26 (d, J=5.6 Hz,1H).

Example 2X-1 Synthesis of salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine

To an alkali solution (41.66 g (sulfone (VI) content 1.66%)) containing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(7.38 g) were added water (64.4 ml), toluene (69.4 ml) and 1-butanol(3.7 ml), which was stirred, then acetic acid (1.98 g) and 5 mol/Laqueous sodium hydroxide solution (0.36 g) were added to adjusted a pHto 9.0. This mixture solution was separated into a toluene layer and awater layer, and the water layer was further extracted with toluene(54.0 ml), and the resulting was combined with the previously extractedtoluene layer. This combined toluene layer was washed with water (25.9ml), and concentrated under a reduced pressure after addition ofcyclopentylamine (5.9 ml). To the resulting residue were addedacetonitrile (58.0 ml) and cyclopentylamine (2.0 ml), which was thenfurther concentrated under a reduced pressure. To the concentratedresidue were added acetonitrile (62.3 ml), cyclopentylamine (11.8 ml)and acetic acid n-butyl ester (54.6 ml), which was stirred at 2° C. Atrace amount of seed crystals (salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine) was added, and after crystal deposition had beenconfirmed this was stirred for 60 minutes at 30° C. (externaltemperature) and cooled to −25° C. (external temperature). The depositwas filtered, washed with acetonitrile (10 ml) chilled at −25° C.(external temperature), and dried under a reduced pressure for about 3hours at room temperature to obtain white crystals of the title compound(8.23 g; yield 90.2%, sulfone (VI) content 0.10%)). The sulfone contentwas confirmed under the same conditions as in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 1.24-1.32 (m, 2H), 1.53-1.59 (m, 2H),1.67-1.73 (m, 2H), 1.79-1.87 (m, 2H), 2.07 (tt, J=6.1, 6.1 Hz, 2H), 2.18(s, 3H), 3.20 (brs, 3H), 3.30-3.38 (m, 1H), 3.35 (s, 3H), 3.54 (t, J=6.1Hz, 2H), 4.09 (t, J=6.1 Hz, 2H), 4.66 (d, J=13.7 Hz, 1H), 4.82 (d,J=13.7 Hz, 1H), 6.73 (d, J=5.6 Hz, 1H), 7.32 (dd, J=3.2, 6.1 Hz, 2H),7.64 (dd, J=3.2, 6.1 Hz, 2H), 8.30 (d, J=5.6 Hz, 1H).

Example 2X-2 Synthesis of a acetone complex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

To a salt (2.51 g (5.6 mmol, sulfone (VI) content 0.10%)) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine were added ethanol (25.1 ml) and ethyl acetate(25.1 ml), which was dissolved at room temperature. To this solution wasadded 5 mol/L aqueous sodium hydroxide solution (1.11 ml), which wasthen concentrated under a reduced pressure. To the resulting residuewere added ethyl acetate (50.2 ml) and acetone (2.5 ml), which wasfurther concentrated under a reduced pressure. Ethyl acetate (18.0 ml)and acetone (12.0 ml) were added to dissolve the resulting dry solid. Tothis mixture solution was added a trace amount of seed crystals (aacetone complex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt), which was stirred overnight at room temperature. Thedeposit was filtered, washed with acetone (7 ml), and dried under areduced pressure at room temperature to obtain white crystals of thetitle compound (2.32 g; 5.3 mmol, yield 93.7%)).

Example 2X-3 Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt (2.04 g (sulfone (VI) content 0.08%)) was obtained by themethods similar to those of WO 2004-085424, Example 6 using an acetonecomplex (2.32 g) of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt.

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1X-3, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 2X-4 Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

To a salt (2.00 g; 4.5 mmol, sulfone (VI) content 0.10%)) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith cyclopentylamine were added water (5.0 ml) and a 5 mol/L aqueoussodium hydroxide solution, which was dissolved by stirring, washed withwater (1.0 ml) and lyophilized. This was then dried under a reducedpressure for about 21 hours at 50° C. to obtain a white solid of thetitle compound (1.81 g; 4.7 mmol, yield 105.2%, sulfone (VI) content0.11%)).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1X-4, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 3X-1 Synthesis of a salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine

To an alkali solution (41.66 g (sulfone (VI) content 1.66%)) containing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole(7.38 g) were added water (64.4 ml), toluene (69.4 ml) and 1-butanol(3.7 ml), which was stirred, acetic acid (1.90 g) was then added toadjust a pH to 9.0. This mixture solution was separated into a toluenelayer and a water layer, and the water layer was further extracted withtoluene (54.0 ml) and the resulting was combined with the previouslyextracted toluene layer. This combined toluene layer was washed withwater (25.9 ml), and concentrated under a reduced pressure afteraddition of sec-butylamine (6.0 ml). To the resulting residue were addedacetonitrile (58.0 ml) and sec-butylamine (2.0 ml), which wasconcentrated again under a reduced pressure. To the concentrated residuewere added acetonitrile (62.3 ml), sec-butylamine (12.3 ml) and aceticacid n-butyl ester (54.6 ml), which was stirred at 12° C. A trace amountof seed crystals (salt of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine) was added, and after cooling to −15° C. (externaltemperature) and confirmation of crystal deposition, this was stirredfor 20 minutes at 20° C. (external temperature) and cooled to −25° C.(external temperature). The deposit was filtered, washed with chilledacetonitrile (10 ml) at −25° C. (external temperature), and dried undera reduced pressure for about 3.5 hour at room temperature to obtainwhite crystals of the title compound (8.10 g; yield 91.3%, sulfone (VI)content 0.02% or less). The sulfone content was confirmed under the sameconditions as in Example 1-1.

¹H-NMR (400 MHz, CDCl₃) δ: 0.91 (t, J=7.4 Hz, 3H), 1.06 (d, J=6.3 Hz,3H), 1.31-1.39 (m, 2H), 2.07 (tt, J=6.1, 6.1 Hz, 2H), 2.18 (s, 3H),2.76-2.84 (m, 1H), 3.13 (brs, 3H), 3.35 (s, 3H), 3.54 (t, J=6.1 Hz, 2H),4.09 (t, J=6.1 Hz, 2H), 4.66 (d, J=13.7 Hz, 1H), 4.82 (d, J=13.7 Hz,1H), 6.73 (d, J=5.6 Hz, 1H), 7.32 (dd, J=3.2, 6.1 Hz, 2H), 7.64 (dd,J=3.2, 6.1 Hz, 2H), 8.30 (d, J=5.6 Hz, 1H).

Example 3X-2 Synthesis of acetone complex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

To a salt (2.61 g (6.0 mmol, sulfone (VI) content 0.02% or less) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine were added ethanol (26.1 ml) and ethyl acetate (26.1ml), which was dissolved at room-temperature. To this solution was added5 mol/L aqueous sodium hydroxide solution (1.14 ml), which was thenconcentrated under a reduced pressure. To the resulting residue wereadded ethyl acetate (52.2 ml) and acetone (2.6 ml), which was thenconcentrated again under a reduced pressure. Ethyl acetate (18.0 ml) andacetone (12.0 ml) were added to dissolve the resulting dry solid. Tothis mixed solution was added a trace amount of seed crystals (acetonecomplex of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt), which was stirred overnight at room temperature. Thedeposit was filtered, washed with acetone (6 ml), and dried under areduced pressure at room temperature to obtain white crystals of thetitle compound (2.36 g; 5.4 mmol, yield 88.9%).

Example 3X-3 Synthesis of2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

2-[{4-(3-Methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt (2.08 g; sulfone (VI) content 0.02% or less) was obtained bythe methods similar to those of WO 2004-085424, Example 6 using anacetone complex (2.36 g) of a2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt.

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1X-3, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Example 3X-4 Synthesis of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolesodium salt

To a salt (2.00 g; 4.6 mmol, sulfone (VI) content 0.02%) of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith sec-butylamine were added water (5.0 ml) and a 5 mol/L aqueoussodium hydroxide solution (0.87 ml), which was dissolved by stirring,washed with water (1.0 ml) and lyophilized. This was then dried under areduced pressure for about 21 hours at 50° C. to obtain a white solid ofthe title compound (1.75 g; 4.6 mmol, yield 99.3%, sulfone (VI) content0.02% or less).

The resulting salt was confirmed from the NMR data to be the same asthat of Example 1X-4, and the sulfone content was confirmed under thesame conditions as in Example 1-1.

Measurement of Powder X-Ray Diffraction Pattern

Powder x-ray diffraction measurements of the salts obtained in theExamples were performed under the following measurement conditions inaccordance with the powder x-ray diffraction measurement methodsdescribed in the general testing methods of the Japanese Pharmacopoeia.

(Equipment)

Rigaku X-ray DTA System: RINT-2000 (Rigaku KK)

(Operating Methods)

Samples were pulverized in an agate mortar, sampled on glass plates, andmeasured under the following conditions.

X-ray used: CuKα Lamp voltage:   40 kV Lamp current:   20 mA Divergenceslit:   1 deg Receiving slit: 0.15 mm Scattering slit:   1 deg Scanningspeed: 2°/min Scanning step: 0.02° Measurement range (2θ): 5 to 40°

FIG. 1 shows the powder x-ray diffraction pattern of the salt obtainedin Example 1X-1, FIG. 2 shows the powder x-ray diffraction pattern ofthe salt obtained in Example 2X-1, and FIG. 3 shows the powder x-raydiffraction pattern of the salt obtained in Example 3X-1. As can be seenfrom the powder x-ray diffraction pattern results in FIGS. 1-3, x-raydiffraction peaks are present in FIGS. 1-3, demonstrating that the saltsof2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith isopropylamine, cyclopentylamine and sec-butylamine of the exampleswere synthesized not in an amorphous state but as salts in a crystallinestate.

INDUSTRIAL APPLICABILITY

According to the present invention, the sulfone of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolecontained as an impurity can be efficiently removed by using salts of2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazolewith amines when manufacturing2-[{4-(3-methoxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H-benzimidazole,which is useful as a drug.

1. A salt represented by the following formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion).
 2. A salt represented by the followingformula (II):


3. A salt represented by the following formula (III):


4. A salt represented by the following formula (IV):


5. A process for manufacturing salt comprising a salt-producing step,wherein the salt-producing step is accomplished in an ester solvent, anitrile solvent, an ether solvent, an alcohol solvent, a ketone solvent,an aliphatic hydrocarbon solvent, an aromatic hydrocarbon solvent, wateror a mixed solvent of the foregoing to produce the salt represented bythe following formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion).
 6. A process for manufacturing a saltcomprising a salt-producing step, wherein the salt-producing step isaccomplished in ethyl acetate, n-butyl acetate, diethyl carbonate,acetonitrile, t-butylmethyl ether, isopropanol, hexane, tetrahydrofuran,toluene or a mixed solvent of the foregoing to produce the saltrepresented by the following formula (I):

(wherein A⁺ represents an isopropylammonium ion, sec-butylammonium ionor cyclopentylammonium ion).